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NM_001267550.2(TTN):c.12016_12019dup (p.Gly4007fs) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 4, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000696708.8

Allele description [Variation Report for NM_001267550.2(TTN):c.12016_12019dup (p.Gly4007fs)]

NM_001267550.2(TTN):c.12016_12019dup (p.Gly4007fs)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.12016_12019dup (p.Gly4007fs)
HGVS:
  • NC_000002.12:g.178741214_178741217dup
  • NG_011618.3:g.94586_94589dup
  • NM_001256850.1:c.11065_11068dup
  • NM_001267550.2:c.12016_12019dupMANE SELECT
  • NM_003319.4:c.10927_10930dup
  • NM_133378.4:c.10361-2857_10361-2854dup
  • NM_133432.3:c.11302_11305dup
  • NM_133437.4:c.11503_11506dup
  • NP_001243779.1:p.Gly3690fs
  • NP_001254479.2:p.Gly4007fs
  • NP_003310.4:p.Gly3644fs
  • NP_597676.3:p.Gly3769fs
  • NP_597681.4:p.Gly3836fs
  • LRG_391:g.94586_94589dup
  • NC_000002.11:g.179605940_179605941insCACT
  • NC_000002.11:g.179605941_179605944dup
  • NM_001256850.1:c.11065_11068dupAGTG
  • NM_001267550.2:c.12016_12019dupAGTGMANE SELECT
Protein change:
G3644fs
Links:
dbSNP: rs1553940935
NCBI 1000 Genomes Browser:
rs1553940935
Molecular consequence:
  • NM_001256850.1:c.11065_11068dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001267550.2:c.12016_12019dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003319.4:c.10927_10930dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133432.3:c.11302_11305dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133437.4:c.11503_11506dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_133378.4:c.10361-2857_10361-2854dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Dilated cardiomyopathy 1G (CMD1G)
Identifiers:
MONDO: MONDO:0011400; MedGen: C1858763; Orphanet: 154; OMIM: 604145
Name:
Autosomal recessive limb-girdle muscular dystrophy type 2J (LGMDR10)
Synonyms:
Limb-girdle muscular dystrophy, type 2J; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10
Identifiers:
MONDO: MONDO:0012127; MedGen: C1837342; Orphanet: 140922; OMIM: 608807

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000825282Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Nov 4, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.

Jansweijer JA, Nieuwhof K, Russo F, Hoorntje ET, Jongbloed JD, Lekanne Deprez RH, Postma AV, Bronk M, van Rijsingen IA, de Haij S, Biagini E, van Haelst PL, van Wijngaarden J, van den Berg MP, Wilde AA, Mannens MM, de Boer RA, van Spaendonck-Zwarts KY, van Tintelen JP, Pinto YM.

Eur J Heart Fail. 2017 Apr;19(4):512-521. doi: 10.1002/ejhf.673. Epub 2016 Nov 3.

PubMed [citation]
PMID:
27813223

Mortality Risk Associated With Truncating Founder Mutations in Titin.

Jansen M, Baas AF, van Spaendonck-Zwarts KY, Ummels AS, van den Wijngaard A, Jongbloed JDH, van Slegtenhorst MA, Lekanne Deprez RH, Wessels MW, Michels M, Houweling AC, Hoorntje ET, Helderman-van den Enden PJTM, Barge-Schaapveld DQCM, Peter van Tintelen J, van den Berg MP, Wilde AAM, Ploos van Amstel HK, Hennekam EAM, Asselbergs FW, Sijbrands EJG, Dooijes D.

Circ Genom Precis Med. 2019 May;12(5):e002436. doi: 10.1161/CIRCGEN.118.002436.

PubMed [citation]
PMID:
31112426
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825282.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Gly4007Glufs*7) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 27813223, 31112426); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 503826). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 11, 2025